1. Field of the Invention
This invention concerns the method for improving the brain function effective for treatment, improvement and prevention of brain metabolic or functional disorders including memory, learning and reflex reaction, symptoms such as Alzheimer's disease, Parkinson's disease and senile dementia associated pathophysiologically with the above disorders, as well as traumatic nervous disorder. The invention also concerns the method for inhibiting glutamate excitotoxicity and rescuing from neuronal death effective for treatment and prevention of glutamic acid-induced brain disorders, e.g. brain apoplexy including brain infarction and hemorrhage, and cerebral ischemia accompanying brain surgery and brain damage.
2. Description of the Prior Art
With the increase in senile population, the number of patients with partial damage in the brain such as senile dementia including Alzheimer's disease and with brain metabolic or functional disorders is increasing.
Various drugs including calcium hopantenate, sodium ozagrel, nilvadipine and anilacetaum have been approved as the brain function improving drugs, which are expected to accelerate brain function in these patients, or to prevent further progress in brain function disroders. Recently, tacrine, an anti-dementia agent, approved in USA has drawn attention.
It is also a known fact that repeated rehabilitation in the patients with partial brain damages results in reconstruction of neural circuit among the remaining neurons and, thus, recovering the brain function.
However, the conventional brain function improving drugs have the problem of causing some adverse reactions. Also, in case of rehabilitation which is not associated with the risk of adverse reaction, it is a trouble to consume a long duration and a great number of training sessions before recovery.
Now, glutamic acid receptors are the most popular receptors present in the brain and their deep association with brain functions such as memory and learning has been known.
The glutamic acid receptors are largely divided into N-methyl-D-aspartic acid (NMDA) receptors and non-NMDA receptors and the effects on NMDA receptors, in particular, are known as an essential factor in the long-term potentiation phenomenon which is a plastic change in the neurons and neural circuit. Moreover, increase in synaptic plasticity including the long-term potentiation is considered essential for fixation of memory and learning and, in fact, there has been a report stating that learning efficienty increased in the long-term potentiated rats. Further, it has been known that the increase in synaptic plasticity including the long-term potentiation is induced by an increase in Ca.sup.2+ concentration in the neurons.
Meanwhile, glutamic acid, although it is associated with memory and learning as an excitable nerve transmitter by affecting glutamic acid receptors, has been known to cause excess excitation of neurons and exhibit neurotoxicity if it is present in excess. For example, it is known that excessive release of glutamic acid accompanying brain embolus or hemorrhage results in successive death of the surrounding neurons by its toxicity.
As glutamic acid antagonists which can alleviate glutamate excitotoxicity, inventions wherein a substance extracted from a spider toxin (Japanese Patent Publication No. 7(1995)-94419, etc.) or a new polyamine compound (Japanese Patent Publication No. 2(1990)-256656, etc.) are used as glutamic acid blockers have been published. Also, an invention utilizing selenite and selenite salts as glutamic acid antagonists has been published (Japanese Patent Publication No. 4(1992)-247033).